Saturday, May 17, 2025
5/17/2025
Immune selection of HIV-1 reservoir cells in human clinical trials - Abstract HIV-1 reservoir cells are a small subset of CD4 T cells that harbor chromosomally integrated HIV-1 DNA, persist life-long and represent the major barrier to a cure of HIV-1 infection. For a long time, proviruses in these cells have been regarded as transcriptionally silent, which permits them to escape from host immune recognition and to resist antiviral host immunity. However, recent studies enabled by single-genome and single-cell analytic technologies have shown that these cells can frequently be transcriptionally active and vulnerable to host immune responses. In line with this observation, our recent work suggested that viral reservoir cells may be subject to immune-mediated host selection forces that promote the elimination of proviruses integrated in permissive chromatin locations supporting active viral transcription, while proviruses in repressive heterochromatin locations appear to have a selection advantage. The central hypothesis of this application is that these naturally occurring immune selection mechanisms can be accelerated through specific immunological interventions that exploit weaknesses and vulnerabilities of HIV-1 reservoir cells. To address this, we propose to apply a panel of novel single-genome/single-cell analytic techniques to analyze HIV-1 reservoir cell evolution in three recently-conducted clinical trials in which different interventional strategies were tested in ART-treated persons. By leveraging existing samples from human interventional studies for such high-resolution analytic approaches, we will be able to identify specific immunological pathways that may be able to effectively target viral reservoir cells, and detect specific susceptibilities and vulnerabilities of the HIV-1 reservoir cell pool that can be exploited in future, more targeted interventions. In specific aim 1, we will use novel single-cell phenotypic profiling technologies to analyze the interplay between viral reservoir cells and autologous innate and adaptive immune effector cells in the ACTIVATE study, a randomized-controlled study focusing on the combined administration of Panobinostat (a potent histone deacetylase inhibitor) with pegylated IFN-α2a. In specific aim 2, we will perform single-cell chromosomal integration site monitoring and phenotyping profiling assays to study HIV-1 reservoir cell evolution in the RIVER study, a randomized-controlled study in which a therapeutic T-cell vaccine was administered in conjunction with vorinostat to individuals with acute HIV-1 infection. In specific aim 3, we will investigate immune selection pressure against HIV-1 reservoir cells in the “kitchen sink study”, a human clinical trial focusing on co-administration of a therapeutic T cell vaccine in conjunction with broadly-neutralizing antibodies and an innate immune modulator (TLR9 agonist). Together, these detailed investigations, involving a series of cutting-edge, single-cell next-generation sequencing approaches, will permit to identify evolutionary selection processes in the viral reservoir cell pool in response to interventional manipulations of human antiviral immune activity and be highly informative for efforts to limit HIV-1 long-term persistence through clinical interventions.
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